Probabilistic control of HIV latency and transactivation by the Tat gene circuit

Cao, Youfang; Lei, Xue; Ribeiro, Ruy M.; Perelson, Alan S.; Liang, Jie

doi:10.1073/pnas.1811195115

Title: Probabilistic control of HIV latency and transactivation by the Tat gene circuit

Journal Article · 18 November 2018 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1811195115 · OSTI ID:1482776

^[1]; Lei, Xue ^[2];

^[3]; Perelson, Alan S. ^[4];

^[2]

Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545,, Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, NM 87545,
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60607,
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545,, Laboratório de Biomatemática, Faculdade de Medicina, Universidade de Lisboa, 1649–028 Lisboa, Portugal
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545,

Significance The reservoir of HIV latently infected cells is the major obstacle for complete eradication of HIV infection. Latency and its transactivation in HIV-infected cells are controlled by the intracellular HIV Tat gene circuit. By reconstructing the probability landscape of the circuit through exact solution of the underlying chemical master equation we examined the detailed mechanism of probabilistic intracellular control of latency and transactivation. We show that while the Tat circuit lacks deterministic bistability its probability landscape exhibits bimodality. Moreover, by exploring changes in the probability landscapes under different perturbations, our study suggests effective therapeutic targets for strategies of “shock and kill” to eliminate latently infected cells and “block and lock” to enforce deep latency.

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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1482776

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 49 Vol. 115; ISSN 0027-8424

Publisher:: Proceedings of the National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: English

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